Probucol is a well-known antioxidant that is related to antioxidant compounds such as 2-(3)-tertiary butyl-4-hydroxyanisole, 2,6-di-tertiary butyl-4-methylphenol and the like. These compounds are used in food and food products to prevent oxidative deterioration.
Probucol is represented by the following structural formula

The preparation of this compound is a multistep process, typically starting by reacting a solution of the appropriately-substituted 4-mercaptophenol with acetone, in the presence of a catalytic amount of a strong acid. Probucol precipitates from the reaction mixture and is readily separated and purified. The reaction is described in detail in U.S. Pat. No. 3,862,332 (Barhhart et al).
Similarly, probucol and certain of its derivatives are also described in U.S. Pat. No. 3,485,843 (Wang), U.S. Pat. No. 3,576,833 (Neuworth) and U.S. Pat. No. 4,985,465 (Handler).
Probucol and its derivatives possess pharmaceutical properties that include antiatherogenesis, lipid lowering and the like. But probucol and numerous of its derivatives are poorly soluble in body fluids.
In order to avoid the low water solubility problems associated with probucol utilization in the body, more water-soluble derivatives have been prepared. Thus, U.S. Pat. No. 5,262,439 (Parthasarathy) discloses a class of water-soluble probucol derivatives having one or more ester groups replacing the phenolic hydroxyl group of the probucol molecule. Some of the compounds disclosed in this reference have polar or charged functionalities attached to the ester group, e.g., the groups carboxylic acid, amide, amino, and aldehyde. The method disclosed for preparing these water-soluble probucol compounds involves the reaction of probucol with the carboxylic acid anhydride compound bearing the desired polar or charged functionality in the presence of a catalyst.
Similarly, U.S. Pat. No. 6,323,359 also discloses water soluble derivatives of probucol. The compounds set forth in this patent are produced by a process involving the reaction of a probucol or the probucol compound with a base, such as an alkali metal or ammonium hydroxide or alkoxide to form a mono or dianion salt. The salt is then reacted with a carboxylic acid anhydrides to produce the desired water soluble derivative of probucol or probucol compound. See also U.S. Pat. No. 6,548,699.
Recently, the preparation of use of certain phosphorous-containing strong bases has been reported. See, for example, U.S. Pat. No. 5,051,533. These compounds, termed prophosphatranes, have the following formula:
wherein R, R′ and R″ are hydrogen or C1 to C8 alkyl.
The prophosphatranes are bicyclic, nonionic bases in which the phosphorous atom functions as the site of electron pair donation. Since the conjugate acid of these compounds have a very high pKa value, the use of prophosphatranes in reactions that have been previously reserved for ionic bases such as sodium hydride, potassium tert-butoxide, etc. have proved fruitful. Thus, prophosphatrane compounds have been shown to be effective in reactions such as dehydrohalogenation, nitroaldol and alcohol silylation. Recently, in the presence of stoichiometric amounts of the prophosphatrane where R and R′ in the above formula are methyl, acetic anhydride (as well as benzoic anhydride) has been shown to react with acid-labile or sterically hindered alcohols to produce acylated alcohols in good yield. See D'Sa et al, J. Org. Chem., 1996, 61, 2963.
The prior art processes used to produce water soluble derivatives of probucol or probucol compounds are disadvantageous, since they are not effective in producing the desired derivatives in any appreciable yields.
The use of prophosphatranes in the preparation of water soluble derivatives of probucol or probucol compounds has not been suggested.
Accordingly, it is desirable to have available a process to efficiently prepare probucol derivatives in high yields.